Lycopene Interferes With Cell Cycle Progression and Insulin-Like Growth Factor I Signaling in Mammary Cancer Cells

Abstract

Recent studies have shown that high insulin-like growth factor I (IGF-I) blood level is a risk factor in breast and prostate cancer. The aim of this study was to determine whether the mitogenic activity of IGF-I in mammary cancer cells can be reduced by the dietary carotenoid lycopene. The anticancer activity of lycopene, the major tomato carotenoid, has been suggested by in vitro, in vivo, and epidemiological studies. Growth stimulation of MCF7 mammary cancer cells by IGF-I was markedly reduced by physiological concentrations of lycopene. The inhibitory effects of lycopene on MCF7 cell growth were not accompanied by apoptotic or necrotic cell death, as determined by annexin V binding to plasma membrane and propidium iodide staining of nuclei in unfixed cells. Lycopene treatment markedly reduced the IGF-I stimulation of tyrosine phosphorylation of insulin receptor substrate 1 and binding capacity of the AP-1 transcription complex. These effects were not associated with changes in the number or affinity of IGF-I receptors, but with an increase in membrane-associated IGF-binding proteins, which were previously shown in different cancer cells to negatively regulate IGF-I receptor activation. The inhibitory effect of lycopene on IGF signaling was associated with suppression of IGF-stimulated cell cycle progression of serum-starved, synchronized cells. Moreover, in cells synchronized by mimosine treatment, lycopene delayed cell cycle progression after release from the mimosine block. Collectively, the above data suggest that the inhibitory effects of lycopene on MCF7 cell growth are not due to the toxicity of the carotenoid but, rather, to interference in IGF-I receptor signaling and cell cycle progression.

Dietary Determinants of Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Proteins 1, -2 and -3 in Women in the Netherlands

“…In three of these studies, higher intake of cooked or processed tomatoes or lycopene was associated with either lower IGF-I levels [14], higher IGFBP-3 levels [22], or a lower IGF-I/IGFBP-3 molar ratio [18]. Two in vitro studies have shown that lycopene can inhibit IGF-I-stimulated growth of endometrium and mammary cancer cell lines [34,35]. In these studies, lycopene reduced IGF-I receptor signaling, and increased levels of membrane-associated IGFBPs [35].…”

“…Two in vitro studies have shown that lycopene can inhibit IGF-I-stimulated growth of endometrium and mammary cancer cell lines [34,35]. In these studies, lycopene reduced IGF-I receptor signaling, and increased levels of membrane-associated IGFBPs [35]. Lycopene supplementation also increased plasma IGFBP-3 concentrations in ferrets [36].…”

“…Additionally, results differed for pre-and postmenopausal women [31], which suggests that the effects of phytoestrogens on the IGF system components may be dependent on endogenous estradiol concentrations. Lycopene is an anti-oxidant mainly found in cooked or processed tomatoes, and has been suggested to interfere with IGF signaling in experimental studies [34][35][36]. Also in cross-sectional studies lycopene [22] or cooked or processed tomatoes [14,18] were associated with IGF-I or IGFBP-3.…”

Tomatoes versus lycopene in oxidative stress and carcinogenesis: conclusions from clinical trials

“…As evident from in vitro and animal studies, purified lycopene may inhibit prostate cancer growth only at higher concentrations, in comparison with tomato antioxidant supplementation. Karas et al (2000) have further reported inhibitory effects of lycopene on MCF7 human mammary cancer cell growth, owing to interference in IGF-1 receptor signaling and cell cycle progression (Karas et al, 2000). Thus, interference in androgen metabolism, and inhibition of growth factors and cytokine activity, appear to be the major pathways through which lycopene inhibits prostate and breast cancer growth.…”

Effect of lycopene supplementation on insulin-like growth factor-1 and insulin-like growth factor binding protein-3: a double-blind, placebo-controlled trial

“…A recent systematic review showed circulating IGF-1 to be associated with increased risk of prostate and pre-menopausal breast cancer (Renehan et al, 2004). A number of studies have suggested a link between lycopene and IGF-1-stimulated cell proliferation in vitro (Levy et al, 1995;Karas et al, 2000), and an inverse association has been demonstrated between cooked tomato consumption and circulating IGF-1 concentrations in vivo (Mucci et al, 2001;Gunnell et al, 2003). Other studies have, however, failed to show an association between circulating IGF-1 and lycopene concentrations (Graydon et al, 2003;Vrieling et al, 2004).…”